Experimental Analysis of Anomalous Pharmacokinetics in Disease State: Pharmacokinetics in Diabetes

疾病状态下异常药代动力学的实验分析：糖尿病的药代动力学

• 批准号: 63571097
• 负责人: KIMURA Toshikiro
• 金额: $ 1.34万
• 依托单位: Okayama University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for General Scientific Research (C)
• 财政年份: 1988
• 资助国家: 日本
• 起止时间: 1988 至 1989
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-63571097/
• 关键词: Diabetes; Streptozotocin; Drug absorption; Drug metabolism; Urinary excretion; Plasma protein binding; streptozotocin

The purpose of this study was to characterize the Pharmacokinetic changes in the diabetic state. The fate of drugs was examined in streptozotocin-induced diabetic rats.1. The intestinal absorption of drugs was increased in the diabetic state, regardless of the absorption characteristics.2. The increased intestinal absorption was caused by the increase in the area of the intestinal mucosa, the increase in the permeability of the brush border membrane and/or the increase in the carrier protein for the active transport in the intestinal mucosa.3. In the case of tolbutamide, while the intestinal absorption was increased in the diabetic state, the AUC following the administration in the intestinal loop was decreased due to the acceleration of the metabolism in the liver.4. The accelerated drug metabolism in the diabetic state seemed to be resulted from the increase in cytochrome P-450 content in the liver.5. Both lowered albumin concentration in the diabetic plasma and increased bematocrit resulted in the increase in the concentration of unbound drug, especially in the case of drugs highly bound to plasma protein.6. Elimination of cepbalexin was accelerated in the diabetic rat, suggesting the enhancement of the urinary excretion process in the diabetic state.In conclusion, while the intestinal absorption is increased in the diabetic state, the elimination processes (metabolism in the liver and urinary excretion) are accelerated, resulting in the unexpectedly poor plasma concentration. On the other hand, there is much possibility of the unexpected side effects in the diabetic state due to the decreased protein binding, caused by lowered albumin concentration in the plasma and decreased plasma volume.

这项研究的目的是表征糖尿病状态的药代动力学变化。在链蛋白酶诱导的糖尿病大鼠中检查了药物的命运1。在糖尿病状态下，药物的肠吸收增加，无论吸收特征如何。2。肠道吸收增加是由肠粘膜面积的增加，刷子边界膜的渗透性增加和/或载体蛋白增加的肠粘膜中有效运输的增加引起的。3。在TOLBUTAMIDE的情况下，虽然糖尿病状态下肠道吸收增加，但由于肝脏中代谢的加速，肠环中给药后的AUC降低了。4。糖尿病状态下的加速药物代谢似乎是由于肝脏中细胞色素P-450含量的增加而产生的。5。两者都降低了糖尿病血浆中的白蛋白浓度和增加的脾气暴伤，导致未结合药物的浓度增加，尤其是在与血浆蛋白高度结合的药物中。6。在糖尿病状态下，糖尿病大鼠的消除加速了糖尿病大鼠，这表明糖尿病状态下的尿排泄过程的增强。结论，虽然糖尿病状态下的肠道吸收量增加，但消除过程（肝脏中的代谢和尿液中的代谢）会导致意外的浓度plasmame plasma却导致了意外的浓度。另一方面，由于蛋白质结合的降低，由于血浆中白蛋白浓度降低和血浆体积降低而导致糖尿病状态的意外副作用很大。